Klinefelter's syndrome (XXY) as a genetic model for psychotic disorders

Lynn E. DeLisi, Andrea M. Maurizio, Christine Svetina, Babak Ardekani, Kamila Szulc, Jay Nierenberg, Jay Leonard, Phillip D. Harvey

Research output: Contribution to journalArticlepeer-review

123 Scopus citations


Males with an extra-X chromosome (Klinefelter's syndrome) frequently, although not always, have an increased prevalence of psychiatric disturbances that range from attention deficit disorder in childhood to schizophrenia or severe affective disorders during adulthood. In addition, they frequently have characteristic verbal deficits. Thus, examining brain magnetic resonance imaging (MRI) scans of these individuals may yield clues to the influence of X chromosome genes on brain structural variation corresponding to psychiatric and cognitive disorders. Eleven adult XXY and 11 age matched XY male controls were examined with a structured psychiatric interview, battery of cognitive tests, and an MRI scan. Ten of eleven of the XXY men had some form of psychiatric disturbance, four of whom had auditory hallucinations compared with none of the XY controls. Significantly smaller frontal lobe, temporal lobe, and superior temporal gyms (STG) cortical volumes were observed bilaterally in the XXY men. In addition, diffusion tensor imaging (DTI) of white matter integrity resulted in four regions of reduced fractional anisotropy (FA) in XXY men compared with controls, three in the left hemisphere, and one on the right. These correspond to the left posterior limb of the internal capsule, bilateral anterior cingulate, and left arcuate bundle. Specific cognitive deficits in executive functioning attributable to frontal lobe integrity and verbal comprehension were noted. Thus, excess expression of one or more X chromosome genes influences both gray and white matter development in frontal and temporal lobes, as well as white matter tracts leading to them, and may in this way contribute to the executive and language deficits observed in these adults. Future prospective studies are needed to determine which gene or genes are involved and whether their expression could be modified with appropriate treatments early in life. Brain expressed genes that are known to escape inactivation on extra-X chromosomes would be prime candidates.

Original languageEnglish (US)
Pages (from-to)15-23
Number of pages9
JournalAmerican Journal of Medical Genetics - Neuropsychiatric Genetics
Volume135 B
Issue number1
StatePublished - May 5 2005
Externally publishedYes


  • Bipolar disorder
  • Cognition
  • DTI
  • MRI
  • Schizophrenia
  • Verbal IQ

ASJC Scopus subject areas

  • Genetics(clinical)
  • Neuropsychology and Physiological Psychology
  • Neuroscience(all)


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